Multiple Sclerosis, Relapsing-Remitting
Conditions
Keywords
RR-MS, Relapsing-Remitting Multiple Sclerosis, Multiple Sclerosis, Synthetic peptide
Brief summary
The IMCY-MS-001 study is a study to test a new experimental drug, IMCY-0141, for the treatment of Relapsing-Remitting Multiple Sclerosis (RR-MS). The pathophysiology of MS with known myelin autoantigens and T cell epitopes makes this disease a particularly attractive indication for development of an immunotherapeutic based on the Imcyse technology. Based on the unique mechanism of action of the drug, IMCY-0141 administered as early as possible after confirmation of the diagnosis may potentially switch-off the autoimmune process and limit the corresponding myelin destruction. Newly (recently) diagnosed patients will be targeted to tackle the disease at its onset. Before launching any efficacy studies, safety of IMCY-0141 in MS patients must be evaluated with a phase I, open-label, dose escalation clinical trial to evaluate the safety of three IMCY-0141 doses followed by a phase II, double-blind, randomized study with an adaptive design to determine if any IMCY-0141 dose(s) offer superior efficacy relative to placebo and to assess immune responses and biomarker data as potential early predictors of efficacy of IMCY-0141 in adults presenting with RR-MS.
Detailed description
The Sample Size determined for this study is as follows: Phase I: A total of 12 patients (4 patients in each of 3 dose cohorts) are planned to be enrolled. The study sample size has been estimated as adequate to provide a reliable safety assessment of the tested doses. All primary, secondary and exploratory endpoints will be summarized by descriptive statistics (continuous variables) or frequency tables (categorical variables), by dose group and overall. Additional patients may be enrolled if requested by the IDMC (Independent Data Monitoring Committee). Phase II: The sample size estimation is based on the total cumulative number of CUAL observed on brain MRI scans from week 12 till week 36. The study sample size has been estimated as adequate to determine if any IMCY-0141 doses offer superior efficacy (as measured by CUAL) relative to placebo. Using the negative binomial model for CUAL, a maximum total of 150 patients are planned to be enrolled (including the 12 patients enrolled in phase I), with 30 patients randomized to each of five groups: * Placebo * IMCY-0141 dose 1 * IMCY-0141 dose 2 * IMCY-0141 dose 3 * DMF (open label) During the adaptive design phase (Phase IIa), a minimum of 40 patients will be enrolled (with 8 patients randomized to each of five groups) and analyzed along with the 12 phase I patients as detailed here: * Placebo: 8 patients * IMCY-0141 dose 1: 8 patients + 4 phase I patients * IMCY-0141 dose 2: 8 patients + 4 phase I patients * IMCY-0141 dose 3: 8 patients + 4 phase I patients * DMF (open label) : 8 patients During the Phase IIb part, up to 98 additional patients will be enrolled in order to get up to 150 patients spread over the groups selected for Phase IIb, with a maximum 30 patients randomized to DMF. These sample sizes are sufficient to deliver Type I errors less than 5% in our chosen null scenarios, and unconditional powers greater than 75% and conditional powers greater than 90% in our two alternative scenarios.
Interventions
DRUGIMCY-0141
The investigational medicinal product (IMP) consists in a small synthetic peptide (23 amino acids - IMCY-0141) combining a known human epitope of MOG flanked with a thioredox motif, presented in the form of a freeze-dried sterile powder and diluent for subcutaneous (SC) administration. The diluent includes the adjuvant aluminium hydroxide (alum) at a concentration of 900 μg/mL. Treatment will be injected within 4h of resuspension of the powder with the diluent. Treatment will consist of 6 immunizations (separated by 14 days) of the IMP by SC injection in the upper arm, in the region of the triceps (lateral part of the arm, midway between the elbow and the shoulder). Half of the dose to be administered will be injected concomitantly in both arms.
DRUGPlacebo
The placebo will be administered by subcutaneous route, once every two weeks for 6 times. Placebo will be administered to patients randomized in the placebo group during Phase II only.
DRUGDimethyl Fumarate
Dimethyl Fumarate (DMF) will be given orally, according to its SmPC for the whole duration of the study. Dimethyl Fumarate (DMF) will be administered to patients randomized in the active control group during Phase II only.
Sponsors
Imcyse SA
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This is a two-step study with a phase I, open-label, dose escalation clinical trial to evaluate the safety of three IMCY-0141 doses followed by a phase II, double-blind, randomized study with an adaptive design to determine if any IMCY-0141 doses offer superior efficacy relative to placebo.
Intervention model description
The study will be conducted under a Bayesian adaptive design approach comprising of two phases: * Phase I where 3 IMCY-0141 doses will be administered following a dose escalation approach. An IDMC safety assessment will allow the escalation from lower to upper dose. * Phase IIa leading to a preliminary estimate of the efficacy of each dose and determination of promising doses. The 2 doses that emerge as most promising will be recommended to advance to Phase IIb, where final efficacy will be judged, again relative to placebo. The least promising dose may be dropped, at the discretion of the trial's IDMC. All told, Phase II will enrol patients who will be randomized to IMCY-0141 or placebo or DMF. At the conclusion of Phase IIb, determined doses will be labelled effective.
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
(Phase I and II): 1. Male or female between 18 and and 45 years old. 2. RR-MS according to the 2017 revisions of the McDonald Criteria. 3. Patients should be newly diagnosed or have a disease duration ≤ 3 years. 4. If not newly diagnosed, patients should have at least one documented clinical relapse in the last 12 months. 5. Patients should present with at least 1 Gadolinium-enhancing (Gd+) T1-weighted lesion OR at least 2 new or enlarging T2-weighted lesions at screening MRI compared to a reference scan in the last 6 months. 6. No background MS treatment at the time of study treatment start (refer to
Exclusion criteria
for details about authorized washout period for some first line treatment). 7. EDSS ≤ 5.0 at screening. 8. Women of childbearing potential (1) should use an highly effective contraception method (2) from screening and for the whole duration of the study. (1) Of child-bearing potential is defined as being post onset of menarche and not meeting any of the following conditions: * Menopausal for at least 2 years (follicle-stimulating hormone within menopausal range), * Having undergone bilateral tubal ligation at least 1 year previously * Having undergone bilateral oophorectomy or hysterectomy. (2) HIGHLY EFFECTIVE contraceptive measures acceptable for the whole duration of the study have been defined based on the CTFGs recommendations on contraception and are the following: * Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), * Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable). * Intrauterine device (IUD) * intrauterine hormone-releasing system (IUS) * Monogamous relationship with vasectomized partner. Partner must have been vasectomized for at least 6 months prior to the patient's entry into the study * Abstinence or absence of sexual relations with men. 9. Ability to understand and comply with research requirements and procedures, in opinion of investigator (Signed Informed Consent)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ph I Primary safety endpoint (2) - Unsolicited injection site and systemic AEs | Up to 36 weeks | Occurrence, intensity and relationship of any unsolicited injection site (local) and systemic AEs occurring throughout the study period. |
| Ph I Primary safety endpoint (4) - Abnormalities on different parameters | Up to 36 weeks | Occurrence and relationship of any abnormality in physical examination, vital signs, 12-lead ECG, MRI, haematological and biochemical laboratory parameters. |
| Ph I Primary safety endpoint (3) - All SAEs | Up to 36 weeks | Occurrence and relationship of all serious adverse events (SAEs) occurring throughout the study period. |
| Ph II Primary efficacy endpoint - Number of CUAL | Week 12 to Week 36 | Total cumulative number of CUAL observed on brain MRI scans (centralized reading) from week 12 till week 36 vs placebo. |
| Ph I Primary safety endpoint (1) - Solicited injection site and systemic AEs | Up to 36 weeks | Occurrence, intensity and relationship of any solicited injection site and systemic adverse events (AEs) during a 7-day follow-up period (i.e., day of study product administration and 6 subsequent days) after each IMCY-0141 administration analysing local injection site and systemic adverse events, clinical and laboratory data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ph II Secondary endpoint (2) - Unsolicited injection site and systemic AEs | Up to 36 weeks | Occurrence, intensity and relationship of any unsolicited injection site (local) and systemic AEs occurring throughout the study period. |
| Ph II Secondary endpoint (3) - All SAEs | Up to 36 weeks | Occurrence and relationship of all serious adverse events (SAEs) occurring throughout the study period. |
| Ph II Secondary endpoint (4) - Abnormalities on different parameters | Up to 36 weeks | Occurrence, intensity and relationship of any abnormality in physical examination, vital signs, 12-lead ECG, MRI, haematological and biochemical laboratory parameters. |
| Ph II Secondary endpoint (1) - Solicited injection site and systemic AEs | Up to 36 weeks | Occurrence, intensity and relationship of any solicited local and systemic adverse event (AE) during a 7-day follow-up period (i.e., day of study drug administration and 6 subsequent days) after each IMCY-0141 administration. |
| Ph I/II Secondary endpoint (1) - Relapse rate | At Week 36 | Annualized relapse rate at week 36 vs baseline |
| Ph I/II Secondary endpoint (2) - Relapse-free rate | At Week 36 | Proportion of relapse-free patients at week 36 vs baseline |
| Ph I/II Secondary endpoint (3) - EDSS Score | At Week 36 | EDSS score at week 36 vs screening |
| Ph I/II Secondary endpoint (4) - Neurofilament light chains levels | Up to 36 weeks | Neurofilament light chains levels in the serum of the patient (sNfL) at baseline, weeks 2, 4, 6, 8, 10, 12, 24 and 36. |
Other
| Measure | Time frame | Description |
|---|---|---|
| To assess the disease activity and the efficacy of IMCY-0141 on MRI parameters and if any IMCY-0141 dose(s) offer superior efficacy. | Up to 36 weeks | Measured by cumulative number of CUAL, number of new Gadolinium-enhancing T1 lesions, number of active (new or enlarging) T2/FLAIR lesions, number of persistent Gadolinium enhancing T1 lesions vs baseline and number of shrinking FLAIR lesions versus baseline. |
| Impact of IMCY-0141 on auto-antibodies against myelin proteins (MOG,PLP) | Up to 36 weeks | Detection of change in MS associated auto-antibodies |
| To evaluate and characterize the MOG-specific CD4+ T cells induced by IMCY-0141 and its impact on autoreactive T-cell responses specific for myelin proteins. | Up to 36 weeks | Changes in cytolytic CD4+ T cell response specific for IMCY-0141, in CD4+ and CD8+ effector T cell responses specific for myelin proteins MOG and/or PLP |
| To assess the disease activity | Up to 36 weeks | Measured by volume change versus baseline in T2/FLAIR lesions, Gadolinium-enhancing T1 lesions, shrinking FLAIR lesions and Brain (White matter, grey matter, cortical grey matter, lateral, thalamus) |
Countries
Moldova
Outcome results
None listed